Clinic-based Screening to Prevent HIV-associated Cryptococcal Mortality

描述(申请人提供)：隐球菌性脑膜炎是全球艾滋病相关死亡的主要原因。循环中的隐球菌抗原可以在神经系统症状出现前几周被检测到，预防性抗真菌治疗可以防止隐球菌脑膜炎和死亡。不幸的是，隐球菌流行地区的大多数诊所无法获得以实验室为基础的隐球菌抗原检测。一种新批准的快速隐球菌抗原测试可以促进在任何资源有限的情况下实施以临床为基础的筛查战略，与口服抗真菌治疗相结合，每年可以拯救全球数千人的生命。然而，需要在临床环境中对隐球菌抗原进行护理点检测的可行性和影响的证据。我的职业目标是成为临床研究的独立研究员，专注于实施科学，以改进隐球菌感染的临床诊断和治疗，并在资源有限的情况下预防隐球菌性脑膜炎。我将利用K23奖项的方法培训，并利用我在南非德班的共同导师和合作者的现有研究基础设施来实现我的科学目标：在资源有限的情况下，更好地了解在艾滋病毒感染成人中进行护理点检测、基于诊所的筛查和实施科学的价值。我的假设是，在最初诊断HIV时，以临床为基础、由护士驱动的护理点筛查隐球菌抗原将是可行的，并将改善患者的预后。我将通过以下四个具体目标来验证这一假设：(1)在护理标准、基于实验室的血清CRAG筛查计划中，估计有和不有隐球菌抗原血症的人在艾滋病毒诊断12个月内的CD4特异性隐球菌抗原血症患病率和隐球菌性脑膜炎的累积发病率和死亡率，(2)通过测量全血和尿样的测试特征来评估快速护理点LFA CRAG测试，与基于黄金标准的血清测试相比，(3)在实施主动的、(1)对新诊断的HIV感染成人进行尿液和/或全血中CRAG的临床筛查，并将隐球菌脑膜炎的累积发病率和死亡率与基于护理标准的实验室血清CRAG筛查计划(在AIM#1中衡量)进行比较，以及(4)评估在南非新诊断的HIV感染成人中强化CRAG筛查与基于实验室的CRAG筛查相比的长期临床结果、成本和成本效益。根据我的教育和指导计划，以及我对结核病护理点诊断测试进行以诊所为基础、由护士驱动的评估的经验，我很有能力实现这些目标。我将借鉴我著名导师和合作者的指导，他们在艾滋病毒护理、隐球菌疾病、临床研究、评估筛查策略和成本效益分析方面拥有丰富的经验，同时也发展了我自己独特的研究轨迹。我的方法是创新的：(1)由护士在临床环境中验证护理点测试，(2)评估基于临床的筛查对患者结局的影响，以及(3)使用一种新的、快速的隐球菌抗原测试平台。拟议的研究具有重要意义，因为它将提供工具，实施基于临床的隐球菌筛查，隐球菌是一种在资源有限的情况下常见且致命的疾病，并为我作为一名独立调查员的职业生涯提供了一个平台。

DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of AIDS-related mortality worldwide. Circulating cryptococcal antigens can be detected weeks before the onset of neurological symptoms, and pre-emptive anti-fungal therapy can prevent cryptococcal meningitis and death. Unfortunately, most clinics in cryptococcal endemic regions do not have access to laboratory-based testing for cryptococcal antigens. A newly-approved, rapid cryptococcal antigen test can facilitate implementing a clinic-based screening strategy in any resource-limited setting, which, when coupled with oral anti-fungal therapy, could save thousands of lives each year worldwide. However, evidence on the feasibility and impact of conducting point-of-care testing for cryptococcal antigens in a clinic-based setting is needed. My career goal is to become an independent investigator in clinical research with a focus on implementation science to improve clinical diagnosis and treatment of cryptococcal infections and prevention of cryptococcal meningitis in resource-limited settings. I will draw upon the methodological training of the K23 award and leverage the existing research infrastructure of my co-mentors and collaborators in Durban, South Africa to accomplish my scientific objective: to better understand the value of point-of-care testing, clinic-based screening, and implementation science for cryptococcal disease among HIV-infected adults in resource-limited settings. My hypothesis is that clinic-based, nurse-driven, point-of-care screening for cryptococcal antigens at the time of initial HIV diagnosis will be feasible and will improve patient outcomes. I will tes this hypothesis through the following four specific aims: (1) To estimate CD4-specific prevalence of cryptococcal antigenemia and cumulative incidence of cryptococcal meningitis and mortality for those with and without cryptococcal antigenemia within 12 months of HIV diagnosis in a standard-of-care, lab-based serum CrAg screening program, (2) To evaluate a rapid point-of-care LFA CrAg test by measuring test characteristics of whole blood and urine samples, compared with gold-standard serum-based tests, (3) To estimate cumulative incidence of cryptococcal meningitis and mortality within 12 months of HIV diagnosis when implementing an active, clinic-based screening program for CrAg in urine and/or whole blood among newly- diagnosed HIV-infected adults, and to compare cumulative incidence of cryptococcal meningitis and mortality to the standard-of-care, lab-based serum CrAg screening program (measured in Aim #1), and (4) To assess the long-term clinical outcomes, cost, and cost-effectiveness of intensified CrAg screening, compared to lab- based CrAg screening, among newly-diagnosed HIV-infected adults in South Africa. I am well positioned to accomplish these aims, based on my educational and mentorship plans, as well as my experience conducting a clinic-based, nurse-driven evaluation of a point-of-care diagnostic test for tuberculosis. I will draw upon the guidance of my renowned mentors and collaborators, who have extensive experience in HIV care, cryptococcal disease, clinical research, evaluating screening strategies, and cost-effectiveness analysis, while also developing my own distinct research trajectory. My approach is innovative by: (1) validating a point-of-care test in a clinical setting by nurses, (2) evaluatig the impact of clinic-based screening on patient outcomes, and (3) use of a novel, rapid cryptococcal antigen testing platform. The proposed research is significant because it will provide the tools to implement clinic-based screening for cryptococcus, a common and fatal disease in resource-limited settings, and provide a platform to launch my career as an independent investigator.